Submissions for variant NM_001127178.3(PIGG):c.901+1del

dbSNP: rs782318668

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002037923	SCV002233353	pathogenic	Intellectual disability, autosomal recessive 53	2022-05-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is also known as c.901+1del. This variant has not been reported in the literature in individuals affected with PIGG-related conditions. This variant is present in population databases (rs782318668, gnomAD 0.03%). This sequence change creates a premature translational stop signal (p.Gly301Valfs*20) in the PIGG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PIGG are known to be pathogenic (PMID: 26996948, 28581210, 28771251).
GeneDx	RCV002284503	SCV002574162	pathogenic	not provided	2022-09-14	criteria provided, single submitter	clinical testing	In vitro functional assays indicate that this canonical splice site variant destroys PIGG expression, resulting in a null allele (Tremblay-Laganiere et al., 2021); This variant is associated with the following publications: (PMID: 31980526, 28771251, 28581210, 26996948, 33763700, 34113002)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002037923	SCV005185089	pathogenic	Intellectual disability, autosomal recessive 53	2024-05-22	criteria provided, single submitter	clinical testing	Variant summary: PIGG c.901+1delG is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.6e-05 in 248268 control chromosomes. c.901+1delG has been reported in the literature in the compound heterozygous and homozygous states in individuals affected with inherited glycosylphosphatidylinositol deficiency (e.g. Duval_2021, Tremblay-Laganiere_2021). These data indicate that the variant is likely to be associated with disease. At least one in vitro study in HEK293 cells shows that this variant results in 0% enzyme activity (e.g. Tremblay-Laganiere_2021). The following publications have been ascertained in the context of this evaluation (PMID: 33763700, 34113002). ClinVar contains an entry for this variant (Variation ID: 1453486). Based on the evidence outlined above, the variant was classified as pathogenic.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002037923	SCV005399777	pathogenic	Intellectual disability, autosomal recessive 53	2024-09-20	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy (MIM#616917). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 9 heterozygotes, 0 homozygotes). (SP) 0311 - Multiple alternative nucleotide changes at the same canonical splice site have been observed in gnomAD (v2 and v3) (highest allele count: 1 heterozygote, 0 homozygotes). (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0705 - No comparable splice variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic in ClinVar and has been reported in both homozygous and compound heterozygous individuals with PIGG-related features (PMIDs: 33763700, 34113002). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. In vitro functional assays show that PIGG/PIGO knock-out cells transfected with the c.901+1del variant compound heterozygous with an NMD-predicted variant, did not rescue PIGG expression (PMID: 34113002). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign